System and method for detecting skin penetration

ABSTRACT

A system and method for detecting skin penetration. The system comprises an invasive component for penetrating the skin; a dummy electrode for making contact with the surface of the skin; at least one penetrating electrode disposed in the invasive component; and a Wheatstone bridge circuit; wherein a resistance across the dummy electrode and the penetrating electrode constitutes one of the resistive legs of the Wheatstone bridge circuit and skin penetration of the invasive component is detected based on a differential output voltage from the Wheatstone bridge circuit.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase of International PatentApplication number PCT/SG2007/000279, filed 24 Aug. 2007, the entirecontents of which are incorporated herein by reference.

FIELD OF INVENTION

The present invention relates broadly to a system and method fordetecting skin penetration.

BACKGROUND

Skin penetration is a common procedure in various biomedicalapplications, particularly in minimally invasive drug delivery (viamicroneedles) where instant detection and/or great precision of skinpenetration is desired. The ability to penetrate the skin reproduciblyto a precise depth enables drugs to be delivered to the desired layers,which is currently the state of the art in transdermal drug delivery(i.e. delivering drug across and into the skin).

Other applications requiring precise control of skin penetration is bodyinterstitial fluid extraction, e.g. blood sampling for blood contentanalysis. Blood sampling involves pricking a body site such as thefinger tip or forearm to obtain a small amount of blood. The amount ofblood is directly related to the wound created by a lancet. Since bloodtesting technology requires less and less blood for accurate testing,there exists a need to precisely control the penetration depth as it isalso directly related to the trauma incurred. The deeper thepenetration, the more traumatic and painful it is.

Lancets are small pointed needles used in pricking the body site toobtain small amount of blood for testing or blood sampling in general.Stainless steel lancets are currently used due to its strength and easeof maintenance. For a typical manufacturing process, a stainless steelwire needs to be cut into correct length and then ground to the desiredsharpness. The cut and ground wire is then inserted into a mold set forinjection molding a plastic component for safety containment andhandling. There are several inherent problems associated with the priorart.

Stainless steel lancets are stiff and hard, and this is a potential riskof injury during the handling or disposal of these lancets. As thelancets are to be destroyed after use, there is a risk of infection.Stainless steel has very high melting temperature (1,420° C.), makingthe incineration process of used lancets very inconvenient forhospitals. There is a need to have lancets that can be functionallydisabled after use. There is also an urgent solution required for theincineration or recycling of these bio-hazardous disposables.

Currently, the blood sampling process involves pricking a body site witha stainless steel lancet and collecting the blood sample using a testmedia such as a plastic test strip. It would be advantageous if thelancet, apart from pricking a body site, can also be used to collect orstore the blood sample and/or then transport it to a location accessiblefor testing means. However, stainless steel having high strength andstiffness is not as suitable a candidate as polymers for incorporatingthese features on the lancet.

As an alternative, lancets are also made of plastic. However, theseplastic lancets merely consist of solid tip for pricking or a channelfor transporting the blood. There are still unsolved problems associatedwith these plastic lancets. Most plastic lancets with transport channelremains in the body for body fluid extraction. This procedure alsocontributes to an increased traumatic experience.

Most existing lancets are unable to perform sensing functions, such asdetecting skin penetration or sensing the depth of penetration. Theability to control the depth of penetration allows pain to be managedeffectively, and it also allows confirmation that a desired depth fordrug delivery is achieved.

On the other hand, there have been several recent proposals to providefor measurements of penetration depth in lancets. However, in most ofthe proposed techniques, the depth of penetration is derived from themeasurement of the absolute electrical characteristics of the skin,which involves correlation of measurements and calibration of equipment.This is imprecise and impractical for transdermal drug delivery.

The electrical properties of skin, change according to environmental andphysiological factors and differ greatly from person to person andbodily regions. Most of the abovementioned proposals merely measure theabsolute values of these properties directly, requiring too manyprecedent correlations before use, which can be impractical. Forexample, those described by US 2002/0042594 entitled “Apparatus andmethod for penetration with shaft having a sensor for sensingpenetration depth” and US 2002/0010414 entitled “Tissueelectroperforation for enhanced drug delivery and diagnostic sampling”do not address the wide variance of the impedance of the skin due tophysiological and environmental factors. Although WO 2004/080306entitled “System and method for piercing dermal tissue” attempts toaddress this issue, by averaging absolute values measured with multiplereference electrodes so as to alleviate the variance in skin impedancedue to humidity, it fails in that it is dependent on many correlationshaving to be performed prior to actual use.

A need therefore exists to provide a system and method for detecting andmeasuring the depth of skin penetration that seeks to address at leastone of the abovementioned problems.

SUMMARY

In accordance with a first aspect of the present invention there isprovided a system for detecting skin penetration, the system comprisingan invasive component for penetrating the skin; a dummy electrode formaking contact with the surface of the skin; at least one penetratingelectrode disposed in the invasive component; and a Wheatstone bridgecircuit; wherein a resistance across the dummy electrode and thepenetrating electrode constitutes one of the resistive legs of theWheatstone bridge circuit and skin penetration of the invasive componentis detected based on a differential output voltage from the Wheatstonebridge circuit.

The system may further comprise a first pair of reference electrodes formaking contact with the surface of the skin, wherein a resistance acrossthe first pair of reference electrodes constitutes the mirroringresistive leg, with respect to ground, of the Wheatstone bridge circuit.

One of the reference electrodes may be the dummy electrode.

The system may further comprise second and third pairs of referenceelectrode, each for making contact with the surface of the skin, whereinrespective resistances across the second and third pairs of referenceelectrodes constitute the remaining resistive legs of the Wheatstonebridge circuit respectively.

A plurality of penetrating electrodes may be disposed in the invasivecomponent.

Resistances across the dummy electrode and the respective penetratingelectrodes may be multiplexed across one of the resistive legs of theWheatstone and a penetration depth of the invasive component is detectedbased on differential output voltages from the Wheatstone bridge circuitfor the respective resistances across the dummy electrode and therespective penetrating electrodes.

The invasive component may comprise a microneedle disposed in a lancingdevice, and the dummy electrode for making contact with the surface ofthe skin is disposed on a skin-contact face of the lancing device.

The invasive component may comprise a microneedle disposed in a lancingdevice, and the dummy electrode for making contact with the surface ofthe skin and the first pair of reference electrodes are disposed on askin-contact face of the lancing device.

The invasive component may comprise a microneedle disposed in a lancingdevice, and the dummy electrode for making contact with the surface ofthe skin and the first, second, and third pairs of reference electrodesare disposed on a skin-contact face of the lancing device.

The invasive component may comprise a hollow or solid microneedle.

The invasive component may comprise a conductive microneedle.

The invasive component may comprise a non-conductive microneedle.

The invasive component may comprises a plastic microneedle.

The system may further comprise means for indicating skin penetration ofthe invasive component based on the differential output voltage from theWheatstone bridge circuit.

The system as claimed in any one of the preceding claims, furthercomprising means for displaying the penetration depth of the invasivecomponent based on the differential output voltages from the Wheatstonebridge circuit.

The reference and/or dummy electrodes may be disposed around an openingof a distal end of the lancing device.

In accordance with a second aspect of the present invention there isprovided a method for detecting skin penetration, the method comprisingthe steps of penetrating the skin with an invasive component wherein atleast one penetrating electrode is disposed in the invasive component;making contact between a dummy electrode and the surface of the skin;applying a resistance across the dummy electrode and the penetratingelectrode as one of the resistive legs of a Wheatstone bridge circuitand; detecting skin penetration of the invasive component is detectedbased on a differential output voltage from the Wheatstone bridgecircuit.

The method may further comprise the steps of making contact with thesurface of the skin with a first pair of reference electrodes; andapplying a resistance across the first pair of reference electrodes asthe mirroring resistive leg, with respect to ground, of the Wheatstonebridge circuit.

One of the reference electrodes is the dummy electrode.

The method may further comprise the steps of making contact with thesurface of the skin with second and third pairs of reference electrode,and applying respective resistances across the second and third pairs ofreference electrodes as the remaining resistive legs of the Wheatstonebridge circuit respectively.

A plurality of penetrating electrodes may be disposed in the invasivecomponent.

Resistances across the dummy electrode and the respective penetratingelectrodes may be multiplexed across one of the resistive legs of theWheatstone and a penetration depth of the invasive component is detectedbased on differential output voltages from the Wheatstone bridge circuitfor the respective resistances across the dummy electrode and therespective penetrating electrodes.

The invasive component may comprise a microneedle disposed in a lancingdevice, and the dummy electrode for making contact with the surface ofthe skin is disposed on a skin-contact face of the lancing device.

The invasive component may comprise a microneedle disposed in a lancingdevice, and the dummy electrode for making contact with the surface ofthe skin and the first pair of reference electrodes are disposed on askin-contact face of the lancing device.

The invasive component may comprise a microneedle disposed in a lancingdevice, and the dummy electrode for making contact with the surface ofthe skin and the first, second, and third pairs of reference electrodesare disposed on a skin-contact face of the lancing device.

The invasive component may comprise a hollow or solid microneedle.

The invasive component may comprise a conductive microneedle.

The invasive component may comprise a non-conductive microneedle.

The invasive component may comprise a plastic microneedle.

The method may further comprise the step of indicating skin penetrationof the invasive component based on the differential output voltage fromthe Wheatstone bridge circuit.

The method may further comprise the step of displaying the penetrationdepth of the invasive component based on the differential outputvoltages from the Wheatstone bridge circuit.

BRIEF DESCRIPTION OF THE DRAWINGS

Embodiments of the invention will be better understood and readilyapparent to one of ordinary skill in the art from the following writtendescription, by way of example only, and in conjunction with thedrawings, in which:

FIG. 1 shows a circuit model for representing the skin impedance;

FIG. 2 shows a simplified circuit model for representing the skinimpedance;

FIG. 3 shows a circuit model representing the skin impedance inaccordance to embodiments of the present invention;

FIG. 4 shows a simplified circuit model representing the skin impedancein accordance to embodiments of the present invention;

FIG. 5 shows a simplified circuit model representing the skin impedancefor DC measurements in accordance to embodiments of the presentinvention;

FIG. 6 shows a simplified circuit model representing the skin impedancefor DC measurements when an electrode is inserted into the skin inaccordance to embodiments of the present invention;

FIG. 7 shows a Wheatstone bridge circuit of the system in accordance toone embodiment of the present invention;

FIG. 8 shows a cross sectional view of the placement of the electrodesin relation to the skin in accordance to one embodiment of the presentinvention;

FIG. 9 shows a modified Wheatstone bridge circuit in accordance to oneembodiment of the present invention;

FIG. 10 shows a simplified modification of the Wheatstone bridge circuitin accordance to the embodiment of the invention of FIG. 9;

FIG. 11 shows another modified Wheatstone bridge circuit in accordanceto one embodiment of the present invention;

FIG. 12 shows a magnified view of a hollow plastic microneedle inaccordance to one embodiment of the present invention;

FIG. 13 shows another magnified view of a hollow plastic microneedle inaccordance to one embodiment of the present invention;

FIG. 14 shows a magnified view of an array of microneedles in accordanceto one embodiment of the present invention;

FIG. 15 shows a front view of an invasive component in accordance to oneembodiment of the present invention;

FIG. 16 shows a cross sectional view of the invasive component of FIG.15 in accordance to one embodiment of the present invention; and

FIG. 17 shows a cross sectional view of the placement of the electrodesin relation to the skin in accordance to one embodiment of the presentinvention.

FIG. 18 shows a flow chart illustrating a method for detecting skinpenetration according to an example embodiment.

DETAILED DESCRIPTION

The described embodiments seek to provide precise control of the depthof skin penetration of an invasive component for delivering a prescribeddrug into a body. There are many instances that require precise skinpenetration. The skin is the largest organ in our body. The skin servesas a protective barrier that insulates our bodies from hostileenvironment. The skin also helps to maintain body temperature for thebody to function well. The body gathers sensory information from theenvironment through the skin. The body also derives its immunity fromdisease through the skin.

There are three layers of skin, namely epidermis, dermis andsubcutaneous tissue. The epidermis is the outer layer of skin havingthickness of roughly 0.05 mm to 1.50 mm. The epidermis is a good targetfor vaccine delivery because it contains antigen-presenting cells (APCs)and is immuno-competent (i.e. after picking up antigens, Langerhanscells migrate and move to the draining lymph nodes). However, suchtransdermal or epidermal vaccination strategy via the epidermis reliesmainly on the ability to precisely deliver the vaccine to the desiredlayer. This remains a major challenge in epidermal vaccination due tothe thinness of the epidermis.

The outermost sublayer, stratum corneum, is made of dead, flat skincells that form an effective insulating layer to protect our body.However, for the purpose of transdermal drug delivery, it is importantto breach the stratum corneum to effectively transport the drugs intothe skin. This poses a great challenge to epidermal vaccination.

The dermis is on average 0.3 mm to 3.0 mm in thickness and contains thetwo sublayers: the papillary and reticular sublayers. The papillarydermis, which is next to epidermis, contains high degree of vascularitynetwork to support the epidermis (which contains very few capillaries)with vital nutrients and also to regulate the temperature of the body byincreasing or decreasing the blood flow in the capillary. Papillarydermis also contains the free sensory nerve endings. This is a gooddelivery site for drug delivery that requires systemic circulation.

The subcutaneous tissue is a layer of fat and connective tissue thathouses larger blood vessels and nerves. This layer is important is theregulation of temperature of the skin itself and the body. The size ofthis layer varies throughout the body and from person to person.

Research has shown that delivering vaccine to the epidermal layer (i.e.second layer after stratum corneum) is more responsive and may requireless quantity. Currently, there is no system that is able to ensurevaccine delivery to epidermis with satisfied reproducibility andprecision.

Transdermal drug delivery has been recognised for more than 20 years butis still limited to drugs that have small molecular size (e.g. <1,000Daltons). There are various penetration enhancers to extend theseapplications to wider drugs, including chemical and electrical (e.g.iontophoresis, electroosmosis, sonophoresis, etc.) means. Microneedlesarise as an effective minimally invasive means to enhance transdermaldrug delivery by breaching the stratum corneum. Notable successes havebeen reported, but there is still a fundamental issue in relation towide acceptance of microneedles, due to the consistency andreproducibility of skin penetration by these tiny needles.

Most of the time, a needle or lancet is inserted into a body to extractbody fluids or for blood testing. More than often, these invasivecomponents are inserted more than required to ensure successfulextraction, thereby incurring unnecessary trauma. Moreover, most lancingdevices in the market do not provide visual access to the lancing site;the user will not know if there is any or enough skin penetrationwithout removing the device from the site. Embodiments of the presentinvention can be tailored to detect and measure momentary skinpenetration.

The impedance of the skin (i.e. the stratum corneum, the epidermis andthe dermis) can be represented with equivalent circuit models comprisingof capacitors and resistors for electrical analysis. The circuit modelas shown in FIG. 1 illustrates that the human skin 124 forms a RC (i.e.resistive-capacitive) network where R₁ 102 and C₁ 104 represent thecombined impedance due to the epidermis and dermis 117. R₂ 106 and C₂108 represent the impedance due to the stratum corneum 116. R₁ 102, R₂106 C₁ 104 and C₂ 108 as shown in FIG. 1 can be further simplified asR_(P) 202 and C_(P) 204 as shown in FIG. 2. Of valuable note is that theimpedance of the stratum corneum in particular, dominates the overallskin impedance.

Embodiments of the present invention attempt to accurately detect skinpenetration and the depth of penetration of an invasive component byimpedance measurement so as to deliver drug treatments at a precisedepth.

In one described embodiment of the present invention, a hollowmicroneedle is used as a lancet to penetrate the skin for bloodsampling. The lancet is also incorporated with one or more penetratingelectrodes to detect and measure skin penetration.

A skin impedance model used in the embodiments of the present inventionis shown in FIG. 3. The model illustrates the human skin 324 (e.g. thestratum corneum 316, the epidermis 318 and the dermis 320) forming a RCnetwork between electrode 312 and electrode 314. The resistance measuredacross the electrode 312 and electrode 314 by the detector 308represents a penetrating resistance R_(PEN). The lateral resistances,R_(EPI) _(—) _(LATERAL) 342 and R_(SC) _(—) _(LATERAL) 346 along theepidermis 318 and stratum corneum 316 respectively, is known to be veryhigh as compared with the rest of the resistive and capacitivecomponents in the model. Contrastingly, the capacitance C_(EPI) _(—)_(LATERAL) 344 and C_(SC) _(—) _(LATERAL) 348 is known to becomparatively low. Hence, the lateral impedance along the epidermis 318and stratum corneum 316 respectively, is negligible and is simplified asshown in FIG. 4. In DC measurements, the capacitive components can bedisregarded such that the equivalent circuit comprises only of resistivecomponents. This further simplification is shown in FIG. 5.

Upon penetrating the skin 324, the invasive component represented by theelectrode 314 breaches past the stratum corneum 316 and enters theepidermis 318, but has not yet breached past the epidermis 318. Sincethe resistance of the stratum corneum 316 is dominant, RPEN reducessignificantly. FIG. 6 shows the equivalent circuit when the electrode314 breaches past the stratum corneum 316 and enters the epidermis 318.The measurement of the penetrating resistance R_(PEN) can be used as anindicator of penetration into the epidermis 318 and dermis 320 from thestratum corneum 316.

FIG. 7 shows an embodiment of the measurement circuit incorporating aWheatstone bridge circuit used to measure the penetration. The circuitcomprises of three matched reference resistors R₁ 702, R₂ 704 and R₃706. The fourth resistance is the penetrating resistance R_(PEN) 708used to measure the penetration of a penetrating electrode. Consider thecase where the reference resistor R₃ 706 have matching resistance equalto the penetrating resistance R_(PEN) 708 at zero skin penetrationdepth, then the voltage potential difference at points V₁ 732 and V₂ 732of the bridge circuit is 0 volts. When the penetrating resistanceR_(PEN) 708 changes due to skin penetration, the bridge circuit isoff-balance and there is now a non-zero voltage potential differencebetween V₁ 730 and V₂ 732. It will be appreciated by a person skilled inthe art that the potential difference is indicative of skin penetrationand this voltage signal can be interfaced to an external circuit forfurther amplification and processing.

However, if the penetrating resistance R_(PEN) 708 is not zeroised tothe value of the reference resistor R₃ 706 at zero penetration depth,there is an offset error voltage created by V₁ 730 and V₂ 732, makingthe detection of the skin penetration erroneous. Such situations canoccur as the skin resistance vary from person to person, site to siteand also fluctuate due to environmental and physiological factors.Correcting the offset error voltage and then correlating it against thepenetration depth to compensate for the error is impractical as itrequires regular calibration effort.

To address the variation in skin resistance in example embodiments, areference resistance measured at a reference site in close proximity tothe penetration site, is used as a “control” during the measurement.Since the reference resistance is preferably taken at a reference sitein close proximity to the penetration site, the variation in resistancebetween the reference resistance and penetration resistance measured iscancelled. The penetration resistance can also be normalised to thereference resistance so that the change is relative instead of absolute.In example embodiments, this can be incorporated into a further modifiedWheatstone bridge circuit.

FIG. 8 shows an example of how the reference site 826, penetration site828 and the skin 824 relate to each other. At the penetration site 828,a penetrating resistance R_(PEN) 808 is measured between a dummyelectrode 812 and a penetrating electrode 814. In a similar manner atthe reference site 826, the reference resistance R_(REF) 806 is measuredbetween the reference electrode 805 and reference electrode 807. Whilethe dummy electrode 812 is usually placed on the skin 824 and thepenetrating electrode 814 penetrates into the skin 824 at thepenetration site 828 for the purpose of measuring the penetration, thereference electrode 805 and reference electrode 807 are usually placedon the skin at the reference site 826 for sole purpose of measuring theskin reference resistance R_(REF) 806 only. The lateral distance betweenthe reference electrode 805 and reference electrode 807 is preferablyequal to the lateral distance between the dummy electrode 812 andpenetrating electrode 814.

FIG. 9 shows how reference resistance R_(REF) 806 is incorporated intothe modified Wheatstone bridge circuit in example embodiments. Thereference resistance R_(REF) 806 can be used to substitute fixedresistor R₃ 808 of FIG. 7. At zero penetration depth, R_(PEN) 808 beingmeasured in close proximity to R_(REF) 806 on the skin 824, isapproximately equal to R_(REF) 806 so that the voltage potentialdifference between V₁ 830 and V₂ 832 is negligibly 0 volts. Offset errorvoltage is minimised and the voltage potential difference between V₁ 830and V₂ 832 directly indicates skin penetration. This embodimentadvantageously solves the variance in skin resistance.

In a further embodiment of the modified Wheatstone bridge circuit asshown in FIG. 10, the circuit can be further simplified. Since the dummyelectrode 812 and the neighbouring reference electrode 807 are at thesame voltage potential, both electrodes can be incorporated as onesingle electrode (i.e. reference cum dummy electrode 811) having thedual function of a dummy electrode 812 and a reference electrode 807.

In another embodiment as shown in FIG. 11, by employing the cancellationeffect of the reference resistance, matched reference resistors R₁, R₂and R₃ (shown in FIG. 7) are totally replaced with reference resistanceR_(REF1) 802, R_(REF2) 804 and R_(REF3) 806 taken at other referencesites in the proximal region of the penetration site. This embodimenteliminates total reliance on stability of the resistance of R₁, R₂ andR₃ but rather on the skin resistance. The reason for this arrangementbeing that resistance drift in R₁, R₂ and R₃ can also cause erroneousmeasurements. The selection of reference resistance R₁, R₂ and R₃ arepreferably comparable in value to the expected skin resistance so thaterror drifts in the resistance of R₁, R₂ and R₃ affects the measurementsas little as possible. In the worst case scenario, when resistance R₁,R₂ and R₃ are large, even a small percentage drift would affect themeasurement by a large amount. By employing reference resistanceR_(REF1) 802, R_(REF2) 804 and R_(REF3) 806 taken at other referencesites in the proximal region of the penetration site, the advantage ofthe cancellation effect is maximised in the embodiment and measurementerrors are minimised.

Embodiments of the invasive component can be made of a singlemicroneedle, or an array of microneedles. These microneedles can besolid (without a lumen) or can be hollow (with at least a lumen fortransport of fluids). The invasive component can be hollow with deliveryholes away from the tip. This allows a sharper tip and reduces thechances of the hole being plugged during the penetration process. Atypical side-ported microneedle with a lumen is shown in FIGS. 12, 13and 14. FIG. 12 shows a magnified view of the tip 1204 and the side port1202 of a hollow plastic microneedle. A further magnified view in FIG.13 shows the tip 1204 and two side ports 1202 from another angle ofview. FIG. 14 shows an array of three non-conductive (plastic)microneedles 1206.

To be used with the invasive component, a conductive wire is insertedfully into the lumen in such as way that the wire is partially exposedto the outside at the side ports. The exposure of the tip of the wire atthe side ports forms the penetrating electrode. The distance between thepenetrating electrode and the apex is determined by the distance of theupper edge of side port to the apex. It will be appreciated by a personskilled in the art that the invasive component can have multiple lumensand multiple wires being inserted to form multiple penetratingelectrodes for the purpose of measuring skin penetration.

A system implementation of the embodiment in FIG. 9 is described now byreferring to FIGS. 15 and 16. This implementation incorporates aninvasive component 1522 and an instrumentation circuitry 1534 into alancing device 1500. A penetrating electrode 1514 to penetrate the skinis disposed on the invasive component 1522. Reference electrode 1505,reference electrode 1507 and dummy electrode 1512 are proximallydisposed on the contact face 1540 of the lancing device 1500. Thereference resistance measured between the reference electrode 1505 andthe reference electrode 1507, constitute one leg of the Wheatstonebridge circuit, which is incorporated into the instrumentation circuitry1534. In a similar manner, the penetrating resistance measured betweenthe dummy electrode 1512 and the penetrating electrode 1514, constitutethe mirror leg of the Wheatstone bridge circuit with respect to ground.It will be appreciated by a person skilled in the art that theimplementation shown in FIGS. 15 and 16 is not limited to the embodimentshown in FIG. 9, but can be a basis for modification to implement theembodiments shown in FIGS. 10 and 11. For example, the dummy electrode1512 can be combined with reference electrode 1505 of same voltagepotential as shown in FIG. 10. Also, the invasive component 1522 canhave multiple penetrating electrodes 1514, form implementation of anembodiment as shown and described below with reference to FIG. 17.

The embodiment in FIG. 17 shows how the depth of penetration of aninvasive component 1722 can be advantageously and accurately measured.The penetration site 178 is the area where skin penetration isperformed. It comprises of a dummy electrode 1712 and one or moreconducting penetrating electrodes 1742, 1744 and 1746 on an invasivecomponent 1722. The dummy electrode 1712 is normally placed in contactwith skin 1724 at the penetration site 1728 and the penetratingelectrodes 1742, 1744 and 1746 are normally disposed on an invasivecomponent 1722, each of which forms an individual resistive loopR_(PEN1) 1741, R_(PEN2) 1743 and R_(PEN3) 1745 with the dummy electrode1712 at the penetration site 1728. While the penetrating electrodes1742, 1744 and 1746 are unique to each resistive loop R_(PEN1) 1741,R_(PEN2) 1743 and R_(PEN3) 1745, only one dummy electrode 1712 at thepenetration site 1728 is necessary for resistance measurement as thepenetrating electrodes 1742, 1744 and 1746 are connected in parallel andterminated at one end at the dummy electrode 1712 and at the other endon the skin 1724 via the invasive component 1722 as shown in FIG. 17.FIG. 17 also shows an example arrangement of the penetrating electrodes1742, 1744 and 1746 on an invasive component 1722 (e.g. microneedle).The resistive loops R_(PEN1) 1741, R_(PEN2) 1743 and R_(PEN3) 1745 arefed to an external measurement circuit for further processing. Eachindividual resistive loop R_(PEN1) 1741, R_(PEN2) 1743 and R_(PEN3) 1745can have a corresponding external unique circuit for resistancemeasurement. However, it is readily apparent to a person skilled in theart, that multiplexing of resistive loops R_(PEN1) 1741, R_(PEN2) 1743and R_(PEN3) 1745 to a single external circuit can be incorporated intoa single measurement system, minimising component count, circuit layout,etc.

In the embodiment in FIG. 17, when the tip of a penetrating electrode1742, 1744 and 1746 has reached the epidermis 1718 beyond the stratumcorneum 1717, the resistive loop R_(PEN1) 1741, R_(PEN2) 1743 andR_(PEN3) 1745 drops from an immeasurable resistance figure (e.g.infinity) to a measurable figure. This property of the reduction inmeasurable resistance figure of the resistive loop R_(PEN1) 1741,R_(PEN2) 1743 and R_(PEN3) 1745 indicates penetration of the respectivepenetrating electrode 1742, 1744 and 1746 into the epidermis 1718. Ifthe penetrating electrodes 1742, 1744 and 1746 are placed atpredetermined distance from each other, penetration depth of theinvasive component 1722 can be determined by detecting which resistiveloops R_(PEN1) 1741, R_(PEN2) 1743 and R_(PEN3) 1745 experience areduction in measurable resistance figure. It is readily apparent to aperson skilled in the art that the detection of the reduction inmeasurable resistance figure can be incorporated onto theinstrumentation circuitry. It is also apparent that the invasivecomponent 1722 in such an embodiment is preferably non-conductive inorder to readily incorporate multiple penetrating electrodes 1742, 1744and 1746. On the other hand, for a single penetrating electrode 1742,the invasive component can be either conductive or non-conductive.

In another embodiment, a display device indicating skin penetrationdepth can also be incorporated into the instrumentation circuitry usinginorganic/organic light emitting diode (LED) or a liquid crystal device(LCD) based display panel. The indication of skin penetration and itsdepth is useful as the user is often obscured from viewing thepenetration site. Such indication allows the user to be informed of thepenetration outcome without taking the lancing device away from thepenetration site.

It will be appreciated by one skilled in the art in the implementationof the instrumentation circuitry, that there can be instances where theresistance change may be detected, but where the resistance change doesnot validly show the penetrating electrode penetrating the skin. Theinstrumentation circuitry in the example embodiments is designed toavoid such incorrect indications. This is described with reference tomodifications to the embodiments in FIGS. 7, 9, 15 and 16, and where V1830 and V2 832 are connected to the instrumentation amplifier 734 at thepositive and negative inputs respectively. The instrumentation amplifier734 is designed such that it only produces a voltage output when thereis a positive voltage difference between the positive and negativeinputs respectively.

Before the lancing device 1500 is in contact with the skin, none of theelectrodes are in contact with the skin 824. Thus, the referenceresistance R_(REF) 806 is at an infinite value. Similarly, thepenetrating resistance R_(PEN) 808 at that stage is also at an infinitevalue. There is no imbalance in the bridge circuit due to the equalityof the differential voltages of V1 830 and V2 832, as both R_(REF) 806and R_(PEN) 808 are infinitely large. The voltage output at theinstrumentation amplifier 734 with respect to ground, would beapproximately zero.

When the lancing device 1500 just makes contact with the skin 824, allof the electrodes except the penetrating electrode 1514 (i.e. referenceelectrodes 1505/1507 and dummy electrodes 1512 only) make contact withthe skin 824. The reference resistance R_(REF) 806 is now measurablebetween reference electrode 1505 and reference electrode 1507. Incontrast, the penetrating resistance R_(PEN) 808 remains unchanged.Thus, there is a voltage imbalance in the bridge circuit due to thedifferential voltages, but because V1 830 and V2 832 would produce anegative voltage difference there would not be any voltage output at theinstrumentation amplifier 734.

When the penetrating electrode 1514 disposed in the invasive component1522, just makes contact with the skin 824, the penetrating resistanceR_(PEN) 808 is reduced to a resistance equal to the reference resistanceR_(REF) 806. The equality of the penetrating resistance R_(PEN) 808 andreference resistance R_(REF) 806, swings the bridge circuit back intobalance. Thus, the voltage output of the instrumentation amplifier 734with respect to ground, would swing back to zero.

When the penetrating electrode 1514 disposed in the invasive component1522 further invades into the skin 824, the penetrating resistanceR_(PEN) 808 is further reduced in resistance than the referenceresistance R_(REF) 806, as it further invades the layers of the skin824, thus producing a positive voltage difference between the positiveand negative inputs of the instrumentation amplifier 734 respectively.The voltage output of the instrumentation amplifier 734 with respect toground, would swing to a positive value as a result, indicative of“true” skin penetration.

It will also be appreciated by a person skilled in the art that thediscussion described above is not limited to the embodiments shown inFIGS. 7, 9, 15 and 16, but is applicable to the implementation of theother embodiments discussed herein.

FIG. 18 shows a flow chart 1800 illustrating a method for detecting skinpenetration according to an example embodiment. At step 1802, the skinis penetrated with an invasive component wherein at least onepenetrating electrode is disposed in the invasive component. At step1804, contact is made between a dummy electrode and the surface of theskin. At step 1806, a resistance is applied across the dummy electrodeand the penetrating electrode as one of the resistive legs of aWheatstone bridge circuit. At step 1808, skin penetration of theinvasive component is detected based on a differential output voltagefrom the Wheatstone bridge circuit.

Embodiments of the present invention aim to detect the change in skinproperty during the skin penetration by an invasive component such as amicroneedle or lancet. In addition, some of the embodiments mentionedcan be readily and advantageously incorporated into polymer lancets.

The electrical properties such as the impedance, the capacitance or theelectrical resistance between two electrodes on the skin are differentcompared to that when one of the electrodes is inserted in the skin. Byincorporating a measurement circuit, the relative change in electricalproperty, such as the electrical resistance, can be measured. Relativechange instead of absolute change is measured as the absolute values ofskin impedance vary according to the bodily, environmental andphysiological factors. This allows the embodiments to be used on anybody without overwhelming calibration and correlation.

To more accurately control the penetration depth, e.g., variouspenetrating electrodes are placed at predetermined positions along theinvasive component's tip, forming points of measurement in oneembodiment. The detection of change in value signifies that a particularelectrode has made contact with respective layers of the inner skin,thereby providing depth of penetration of the invasive component.

By making use of detection circuitry, the embodiments can providevarious means of controlling the insertion actuation, thereby providingan accurate and reliable means to determine the depth of skinpenetration. Combined with other instrumentation, readouts can bedisplayed and preferably make the usage more intuitive.

The proposed system can combine the various embodiments described andincorporate into a single lancing device, enabling an integratedone-step blood testing device. For example, a lancing device withfeatures to automate skin penetration depth while displaying skinpenetration/depth on the display LCD/LED and onboard bloodsampling/analysis test circuitry after collection of the blood samples.The lancing device can also deliver a precise amount of drug to adefined skin depth and display the delivery progress.

It will be appreciated by a person skilled in the art that numerousvariations and/or modifications may be made to the present invention asshown in the specific embodiments without departing from the spirit orscope of the invention as broadly described. The present embodimentsare, therefore, to be considered in all respects to be illustrative andnot restrictive.

We claim:
 1. A system for detecting skin penetration, the systemcomprising: an invasive component for penetrating the skin; a dummyelectrode for making contact with the surface of the skin; at least onepenetrating electrode disposed in the invasive component; a Wheatstonebridge circuit; wherein a resistance across the dummy electrode and thepenetrating electrode constitutes one of the resistive legs of theWheatstone bridge circuit, and a first pair of reference electrodes formaking contact with the surface of the skin, wherein a skin resistanceacross the first pair of reference electrodes constitutes the mirroringresistive leg, with respect to ground, of the Wheatstone bridge circuit;wherein the system is configured to detect a depth of skin penetrationof the invasive component based on a differential output voltage fromthe Wheatstone bridge circuit.
 2. The system as claimed in claim 1,wherein one of the reference electrodes is the dummy electrode.
 3. Thesystem as claimed in claim 1, further comprising second and third pairsof reference electrodes, each for making contact with the surface of theskin, wherein respective skin resistances across the second and thirdpairs of reference electrodes constitute the remaining resistive legs ofthe Wheatstone bridge circuit respectively.
 4. The system as claimed inclaim 1, wherein a plurality of penetrating electrodes are disposed inthe invasive component.
 5. The system as claimed in claim 4, whereinresistances across the dummy electrode and the respective penetratingelectrodes are multiplexed across one of the resistive legs of theWheatstone bridge circuit connected to the respective penetratingelectrodes, and the depth of skin penetration of the invasive componentis detected based on differential output voltages from the Wheatstonebridge circuit induced by the respective resistances across the dummyelectrode and the respective penetrating electrodes.
 6. The system asclaimed in claim 1, wherein the invasive component comprises amicroneedle disposed in a lancing device, and the dummy electrode formaking contact with the surface of the skin is disposed on askin-contact face of the lancing device.
 7. The system as claimed inclaim 1, wherein the invasive component comprises a microneedle disposedin a lancing device, and the dummy electrode for making contact with thesurface of the skin and the first pair of reference electrodes aredisposed on a skin-contact face of the lancing device.
 8. The system asclaimed in claim 3, wherein the invasive component comprises amicroneedle disposed in a lancing device, and the dummy electrode formaking contact with the surface of the skin and the first, second, andthird pairs of reference electrodes are disposed on a skin-contact faceof the lancing device.
 9. The system as claimed in claim 1, wherein theinvasive component comprises a hollow or solid microneedle.
 10. Thesystem as claimed in claim 1, wherein the invasive component comprises aconductive microneedle.
 11. The system as claimed in claim 1, whereinthe invasive component comprises a non-conductive microneedle.
 12. Thesystem as claimed in claim 11, wherein the invasive component comprisesa plastic microneedle.
 13. The system as claimed in claim 1, furthercomprising means for indicating the depth of skin penetration of theinvasive component based on the differential output voltage from theWheatstone bridge circuit.
 14. The system as claimed in claim 1, furthercomprising means for displaying the depth of skin penetration of theinvasive component based on the differential output voltages from theWheatstone bridge circuit.
 15. The system as claimed in claim 6, whereinthe reference and/or dummy electrodes are disposed around an opening ofa distal end of the lancing device.
 16. A method for detecting skinpenetration, the method comprising the steps of: penetrating the skinwith an invasive component wherein at least one penetrating electrode isdisposed in the invasive component; making contact between a dummyelectrode and the surface of the skin; applying a resistance across thedummy electrode and the penetrating electrode as one of the resistivelegs of a Wheatstone bridge circuit; making contact with the surface ofthe skin with a first pair of reference electrodes; applying a skinresistance across the first pair of reference electrodes as themirroring resistive leg, with respect to ground, of the Wheatstonebridge circuit; and detecting a depth of skin penetration of theinvasive component based on a differential output voltage from theWheatstone bridge circuit.
 17. The method as claimed in claim 16,wherein one of the reference electrodes is the dummy electrode.
 18. Themethod as claimed in claim 16, further comprising the steps of: makingcontact with the surface of the skin with second and third pairs ofreference electrodes, and applying respective skin resistances acrossthe second and third pairs of reference electrodes as the remainingresistive legs of the Wheatstone bridge circuit respectively.
 19. Themethod as claimed in claim 16, wherein a plurality of penetratingelectrodes are disposed in the invasive component.
 20. The method asclaimed in claim 19, wherein resistances across the dummy electrode andthe respective penetrating electrodes are multiplexed to one of theresistive legs of the Wheatstone bridge circuit connected to therespective penetration electrodes and the depth of skin penetration ofthe invasive component is detected based on differential output voltagesfrom the Wheatstone bridge circuit induced by the respective resistancesacross the dummy electrode and the respective penetrating electrodes.21. The method as claimed in claim 16, wherein the invasive componentcomprises a microneedle disposed in a lancing device, and the dummyelectrode for making contact with the surface of the skin is disposed ona skin-contact face of the lancing device.
 22. The method as claimed inclaim 16, wherein the invasive component comprises a microneedledisposed in a lancing device, and the dummy electrode for making contactwith the surface of the skin and the first pair of reference electrodesare disposed on a skin-contact face of the lancing device.
 23. Themethod as claimed in claim 18, wherein the invasive component comprisesa microneedle disposed in a lancing device, and the dummy electrode formaking contact with the surface of the skin and the first, second, andthird pairs of reference electrodes are disposed on a skin-contact faceof the lancing device.
 24. The method as claimed in claim 16, whereinthe invasive component comprises a hollow or solid microneedle.
 25. Themethod as claimed in claim 16, wherein the invasive component comprisesa conductive microneedle.
 26. The method as claimed in claim 16, whereinthe invasive component comprises a non-conductive microneedle.
 27. Themethod as claimed in claim 26, wherein the invasive component comprisesa plastic microneedle.
 28. The method as claimed in claim 16, furthercomprising the step of: indicating the depth of skin penetration of theinvasive component based on the differential output voltage from theWheatstone bridge circuit.
 29. The method as claimed in claim 20,further comprising the step of: displaying the depth of skin penetrationof the invasive component based on the differential output voltages fromthe Wheatstone bridge circuit.